Complex Spinal Paraspinal Fast Flow Lesions in CLOVES Syndrome: Analysis of Clinical and Imaging Findings in 6 Patients

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CLINICAL REPORT

Complex Spinal-Paraspinal Fast-Flow Lesions in

CLOVES Syndrome: Analysis of Clinical and

Imaging Findings in 6 Patients

A.I. Alomari G. Chaudry G. Rodesch P.E. Burrows J.B. Mulliken E.R. Smith S.J. Fishman D.B. Orbach

SUMMARY: CLOVES syndrome is a complex disorder of congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies. We report the occurrence of spinal-paraspinal fast-flow lesions within or adjacent to the truncal overgrowth or a cutaneous birth-mark in 6 patients with CLOVES syndrome.

ABBREVIATIONS:AVM⫽arteriovenous malformation; CLOVES syndrome⫽congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal/scoliosis/spinal anomalies

S

everal overgrowth syndromes are associated with vascular

anomalies; the best know are Klippel-Trenaunay

syn-drome and Parkes Weber synsyn-drome. Vascular anomalies also

have been reported in Proteus syndrome.

1,2

Subsequent

clin-ical studies have shown that many patients once labeled with

Proteus syndrome have a newly characterized overgrowth

condition known by the acronym CLOVES, as described by

Sapp et al

3

and Alomari.

4

Multiple, often marked, anomalies

make the management of patients with CLOVES syndrome

particularly difficult. Furthermore, a subgroup in our

CLOVES syndrome cohort was noted to have a debilitating

spinal myelopathy due fast-flow spinal-paraspinal vascular

le-sions. Our aim was to report the clinical presentation and

im-aging features of this morbid association.

Case Reports

This study was approved by our Committee on Clinical Investigation. Six of the 26 patients with CLOVES syndrome were identified as hav-ing complex spinal-paraspinal fast-flow lesions. The available imag-ing studies included MR imagimag-ing in 6 patients, CT in 4, and spinal angiography in 5. Each patient is described below to emphasize the clinical course and imaging findings.

Patient 1

A 4-year-old girl presented to the emergency department of our hos-pital with a sudden onset of painless weakness of the left upper ex-tremity and absent biceps reflexes. Her medical history was significant for a prenatal diagnosis of a complex lymphatic malformation of the right axilla and chest wall seen at 16 weeks’ gestation. She was deliv-ered via cesarean delivery. Truncal overgrowth was massive (Fig 1A) and continued to enlarge postnatally. A CT study demonstrated ex-tensive fatty-lymphatic infiltration throughout the chest wall, axilla,

and posterior mediastinum. At 3 months of age, she underwent par-tial resection of the truncal mass. At 9 months of age, she presented with a rapidly enlarging fatty mass of the abdominal wall, which was resected.

Urgent MR imaging was performed and demonstrated an expan-sile hemorrhagic nonenhancing intramedullary lesion within the cer-vical spinal cord from the C4 to C6 levels (Fig 1B). There was a large infiltrative fatty and lymphatic lesion within the posterior mediasti-num, right axilla, and chest wall (Fig 1C). Large fast-flow vessels were noted in the mediastinal-paravertebral portion of this mass.

She was initially given corticosteroids and improved neurologi-cally. The interdisciplinary recommendation was no urgent interven-tion, given the high risk.

During the following year, the patient had 3 more hemorrhagic episodes in the same spinal region causing transient increased left-arm weakness, incontinence, and some clumsiness of the gait. Given the ongoing episodes, the spinal lesion was excised, with a histopatho-logic diagnosis of cavernous (venous) malformation. The patient had residual proximal left-arm weakness.

Follow-up MR imaging revealed the development of large flow voids in the paraspinal mass that insinuated intraspinally via midcer-vical neuroforamina. Angiography revealed a paraspinal-epidural AVM, with drainage into enlarged epidural veins, which compressed the cord (Fig 1D). She underwent staged embolization and surgical removal of the AVM nidus. The histopathologic examination re-vealed markedly dilated blood vessels surrounded by abundant he-mosiderin and hyalinization of the wall.

Patient 2

A white teenage boy had an asymmetric torso and extremities, with left hemihypertrophy. Capillary stains and melanocytic nevi were noted along the left paraspinal and gluteal area (Fig 2A). Some of these patches concomitantly displayed the appearance of a port-wine stain (capillary malformation). There was an extensive linear epidermal nevus on the right shoulder and anterior chest wall, which followed the lines of Blaschko (Fig 2B). A spinal MR imaging study showed extensive flow voids within and around the lower third of the spinal cord around the T10-L1 vertebral bodies (Fig 2C). The dilated chan-nels on the surface of the cord represented a dilated posterior pial arterial network. The adjacent dilated intradural radicular veins drained the lesion transdurally into the ipsilateral paraspinal region via the widened neuroforamina. Deformity and abnormal hyperin-Received February 14, 2010; accepted after revision August 23.

From the Division of Vascular and Interventional Radiology (A.I.A., G.C., D.B.O.), Vascular Anomalies Center (A.I.A., G.C., J.B.M., S.J.F. D.B.O.), Departments of Plastic Surgery (J.B.M.), Neurosurgery (E.R.S.), and Surgery (S.J.F.), Children’s Hospital Boston and Harvard Medical School, Boston, Massachusetts; Department of Diagnostic and Therapeutic Neu-roradiology (G.R.), Hoˆpital Foch, Paris, France; and Department of Diagnostic Imaging (P.E.B.), Texas Children’s Hospital, Houston, Texas.

Please address correspondence to Ahmad I. Alomari, MD, MSc, Division of Vascular and Interventional Radiology, Children’s Hospital Boston, 300 Longwood Ave, Boston, MA 02115; e-mail: ahmad.alomari@childrens.harvard.edu

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tense signal-intensity changes in the L2 vertebral body resulted in a local lumbar kyphosis.

Spinal angiography showed a metameric shunt supplied predom-inantly by radiculopial branches from the lower thoracic intercostal arteries (Fig 2D). Additional supply was recruited from enlarged pial branches of a radiculomedullary artery from a left upper lumbar ar-tery. The drainage was into an extensive dilated perimedullary pial network on the surface of the cord and markedly ectatic extradural veins.

Patient 3

A 17-year-old white boy was referred with the diagnosis of Klippel-Trenaunay syndrome. He was born with extensive vascular malfor-mations of the legs and spine (Fig 3A) and had a history of seizures

and upper gastrointestinal bleeding. A few months earlier, he had developed sharp back pain, urinary incontinence, fatigue, and dys-pnea. Pulmonary embolism was excluded by CT angiography. On physical examination, there was overgrowth of both lower extremities and the dorsal trunk, with right paraspinal overgrowth covered by a large faint capillary stain, a facial epidermal nevus, and multiple-toe macrodactyly. Moderate scoliosis and a sharp-degree thoracolumbar kyphosis were also evident. Ambulation was limited as a result of advanced right-hip developmental dysplasia, and he used a wheel-chair. Spinal MR imaging showed an extensive lumbosacral fatty overgrowth in the paraspinal region and asymmetric paraspinal mus-cles (Fig 3B). There were flow-void signals within the mass with ex-tension into the spinal canal and erosion of at least 1 lamina. A large epidural venous channel was seen inside the lumbosacral spinal canal, Fig 1.A, Frontal photograph before the first surgical debulking. A large truncal mass extends into the right axilla, chest, and upper abdominal walls. Note a faint capillary malformation overlying the mass.B, Sagittal T2 MR image of the cervicothoracic spine demonstrates an expansile heterogeneous intramedullary lesion within the cervical spinal cord from the C4 to C6 levels, with signal-intensity characteristics consistent with blood products. A ventral cord lesion demonstrates a fluid-fluid level indicating an acute parenchymal hematoma (arrow). Perilesional T2 hyperintense rim is consistent with edema.C, Sagittal T2 MR image shows a diffuse involvement of the mediastinum and the paraspinal musculature with lymphatic malformation (white arrow) and fatty tissue, with marked deviation and compression of the spinal cord. There is an asymmetric fatty overgrowth of the spinal canal with the subcutaneous layer (bent arrow) insinuating into it via the neuroforamina, with large flow-void signals (notched arrow).D, Right vertebral arteriogram. The arterial supply to the epidural portion comes via the C3, C4, and C5 segmental branches of the right vertebral artery. The anterior and posterior spinal arteries are unremarkable. The lesion drains into markedly dilated epidural veins coursing inferiorly within the spinal canal and exits at a left upper thoracic neural foramen.

PEDIATRICS

CLINICAL

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almost equal in size to the thecal sac. The cord was tethered, with the conus terminating at the L4 level. There was compression of the conus medullaris and thecal sac along most of the lumbar and sacral regions and a Chiari 1 malformation. The paraspinal muscles were extensively infiltrated with a large conglomerate of vessels in a fatty substance.

Sonography of the urinary bladder showed significant postvoid

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kiewicz (left T11, Fig 3D). Venous drainage was via epidural and intrathecal veins ascending to the lower thoracic region.

Patient 4

A 3-year-old boy from Brazil was referred to our Vascular Anomalies Center with the diagnosis of the truncal form of Klippel-Trenaunay syndrome. The child was born with a large soft-tissue overgrowth of the back. There were capillary stains on the chest wall, forehead, and occipital areas. The left foot was large at birth and had grown

propor-tionally since. The sole of the left foot had a furrowed appearance, and the first interdigital space was abnormally wide (sandal-gap toe). MR imaging showed an expansive infiltrative lesion with heterogeneous signal intensity located in the left paravertebral musculature with ex-tension into the left retroperitoneal, pelvic, and gluteal areas. Fatty tissue and large vessels extended into the epidural space displacing the spinal cord. There was a small syrinx. Scoliosis and renal asymmetry were also noted.

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pathologic examination revealed complex benign tissue with lym-phatic malformation and infiltrative hamartomatous tissue associ-ated with arteriovenous fistulas. With time, there has been significant regrowth of the lesion.

Patient 5

A 4-year-old white girl was referred with a diagnosis of AVM-hem-angioma-angiolipoma involving the left side of her trunk. She was born with capillary stains on both paraspinal regions. Retroperito-neal, pelvic, and gluteal extension of the paraspinal lesion was noted, and scoliosis was evident. The patient had a gait disturbance, with dysfunction of the right leg and a limb-length discrepancy. Occasion-ally, she felt some back pain with physical activity. She underwent resections of the lesion after preoperative embolization. CT of the trunk showed a large left paraspinal overgrowth composed largely of fat extending into the adjacent retroperitoneal and spinal canal. There was expansion of the spinal canal and some displacement of the cord in the lower thoracic area. Spinal angiography showed arteriovenous shunt surgery involving the overgrown paraspinal area as well as the vertebral body, with intradural and extradural drainage.

Patient 6

A 2-year-old girl was born with massive bilateral truncal overgrowth and extensive involvement of the chest wall, flank, axillae, and ante-rior abdominal wall with overlying capillary stains. There was asym-metric overgrowth of the lower extremities and gluteal areas with enlargement of the feet, macrodactyly, and syndactyly. The lower ex-tremities progressively became paraparetic and spastic; contractures caused an inability to walk. There was notable cognitive delay. Skeletal anomalies included scoliosis and bilateral hip dysplasia. MR imaging showed extensive truncal overgrowth comprising predominantly fatty and lymphatic tissue, extending into the mediastinal, abdomi-nal, and pelvic spaces. The left kidney was small. Spinal angiography at our hospital showed extensive hypervascularity and arteriovenous shunt surgery in the paraspinal soft tissues between the T2 and T5 levels, with extension into the epidural space. The arterial feeders arose from numerous small branches of the segmental arteries with epidural drainage into the azygous vein.

After preoperative embolization, shunt surgery through the in-traspinal portion was almost completely eliminated. Thereafter, cord compression by the intraspinal vascular tissue and lack of spinal cord function below the affected level necessitated exploration and T1-T5 laminectomy. Hypervascular tissue found in the intradural-ex-tramedullary space communicated with the pial vessels. The debili-tating course of the disease resulted in paraparesis, chronic pain, sei-zures, learning disabilities, malnourishment, chronic constipation, and urine incontinence.

Discussion

CLOVES syndrome is a recently described sporadic

over-growth disorder with features of truncal fatty overover-growth,

vas-cular malformations, epidermal nevus, and skeletal anomalies

(including scoliosis and variable acral anomalies).

1,2

Patients

with CLOVES syndrome are typically born with lipomatous

masses of the thoracic and abdominal wall (commonly in the

posterolateral chest wall and flank) with variable contiguous

extension to the anterior abdominal wall, groin,

retroperito-neum, mediastinum, and gluteal area. Slow-flow vascular

mal-formations (including lymphatic malmal-formations and

phlebec-tasia) are common.

4

Other manifestations of the syndrome

include musculoskeletal (leg-length discrepancy,

chondroma-lacia patellae, dislocated knees, scoliosis, wide hands and feet,

furrowed soles, sandal-gap toe, macrodactyly, talipes,

wind-swept hand, hemihypertrophy), neurologic (neural tube

de-fect, tethered cord), cutaneous (capillary malformation,

epi-dermal nevus, multiple small nevi), and other anomalies (such

as renal agenesis/hypoplasia).

Spinal cord arteriovenous shunts are a rare and

heteroge-neous group of vascular anomalies. Although the natural

his-tory of these lesions is variable, the overall prognosis is

consid-ered unfavorable.

5

An exceedingly rare form of arteriovenous

shunt, located outside the spinal canal, can potentially result in

spinal cord injury (ie, a paraspinal or paravertebral AVM with

epidural venous drainage).

6

Draining via the epidural venous

plexus into spinal cord veins can potentially result in venous

hypertension and myelopathy.

7

In a review of the cohort of patients with CLOVES

syn-drome at Children’s Hospital Boston, Alomari

4

described the

presence of spinal-paraspinal fast-flow lesions in 5 of 18

pa-tients. The spinal column can be affected in several ways in

patients with CLOVES. Direct insinuation of the mass

through the neuroforamina into the epidural space can

com-press the cord, thecal sac, or nerve roots. Parasitization of

blood supply from segmental feeders (both pial and, more

commonly, nonpial branches) has also been noted to follow

the distribution of the fatty-lymphatic overgrowth. Engorged

dilated dural veins within the spinal canal can also cause mass

effect. In the rare paravertebral AVMs, such as seen in

CLOVES syndrome, venous hypertension in the paravertebral

plexus may affect the spinal cord through reflux into the pial

veins via an epidural route, causing compromise of the cord

function.

8

Other spinal comorbidities in CLOVES syndrome

include scoliosis, vertebral anomalies, neural tube defects, and

tethered cord.

The treatment of spinal AVMs is a neurosurgical

chal-lenge.

9

Resection of the fatty truncal mass in CLOVES

syn-drome, if feasible, is associated with recurrence.

4

Endovascu-lar techniques can be helpful in controlling the flow in AV

shunts and alleviating symptoms in some of these lesions, as

well as being a useful adjunct to resection.

6

Some of the cardinal features of CLOVES syndrome may

appear to overlap other overgrowth disorders, such as

Klippel-Trenaunay syndrome, Cobb syndrome, Proteus syndrome,

and Parkes Weber syndrome. Bannayan-Riley-Ruvalcaba

syn-drome and Lhermitte-Duclos disease (2 rare synsyn-dromes

re-sulting from mutation in the

PTEN

gene) also have been

re-ported to have paraspinal arteriovenous shunts.

10,11

Many of

the case reports presumed to be examples of Cobb syndrome

are more likely examples of CLOVES syndrome.

8,12-17

The

in-dex case by Stanley Cobb in 1915 described the association of

a cutaneous nevus and a spinal AVM in the same metamere.

18

Since then, the Cobb syndrome diagnosis has been

indiscrim-inately applied to various pathologies in which a spinal AVM

and cutaneous lesions coexist.

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tor-tuous dilated perimedullary veins. Spinal MR imaging

re-vealed a lumbosacral fatty mass with extension into the spinal

canal, spina bifida, and tethered cord. Zala and

Mumentha-ler

13

described a case of presumed Cobb syndrome in which

the patient demonstrated hemihypertrophy, verrucous

angi-oma, and cafe´ au lait spots. Clinton et al

14

reported a boy with

a verrucous vascular malformation of the right chest and

up-per back associated with a symptomatic “cavernous” vascular

malformation in the corresponding thoracic spinal cord. Shim

et al

15

associated Cobb syndrome with lymphangioma

cir-cumscriptum. Brant et al

16

reported an interesting case of a

neonate girl born with a large subcutaneous mass covered by a

cutaneous hemangioma of the lumbosacral region.

Ratzen-hofer et al

17

described spinal arteriovenous shunts and spinal

angiomas, linear epidermal nevus, leg length discrepancy, and

other pedal and osseous changes in a 12-year-old boy.

Beren-stein et al

8

also referred to a large pulsatile mass of the right

paraspinal mass associated with a purely extraspinal AVM.

Analysis of these cases involving truncal fatty masses

(lipome-ningocele, paraspinal mass), lymphatic lesions

(lymphangi-oma circumscriptum, verrucous vascular lesions), other

cuta-neous lesions (linear epidermal nevus, hemangioma), and

musculoskeletal anomalies (hemihypertrophy, foot

anoma-lies) suggests that they are all likely to be examples of CLOVES

syndrome.

The etiology of overgrowth syndromes associated with

vas-cular anomalies, including CLOVES, is largely unknown.

These rare sporadic and asymmetric phenotypes could result

from genetic mutations, which, in autosomal form, would be

lethal but which survive through mosaicism, as proposed by

Happle.

19

The coexistence of fatty overgrowth and fast-flow

shunts in CLOVES syndrome is further evidence of a strong

relation between the adipocytes and the endothelial cells. The

pioneering work of Rupnick et al

20

and Folkman

21

showed

that adipose tissue growth is angiogenesis-dependent and

an-giogenesis inhibitors cause decreased endothelial cell

prolifer-ation and increased apoptosis in the adipose tissue of treated

animals. The angioarchitecture of these complex shunts

dis-plays a metameric disposition with arterial feeders derived

from consecutive segmental arteries.

This retrospective analysis relied on available data

regard-ing a new rare disorder. Not all the subjects in the CLOVES

cohort were evaluated for the presence of paraspinal shunts.

Specifically, relevant diagnostic studies, such as spinal

angiog-raphy and MR imaging, were not performed or available in all

patients. The presence of other spinal abnormalities in

CLOVES (such as paraspinal masses, tethered cord, nerve and

cord compression, kyphoscoliosis, skeletal anomalies, and so

forth) could also account for some of the patients’ signs and

symptoms, precluding further imaging work-up. These

limi-tations might result in an underestimation of the true

inci-dence of the vascular paraspinal lesions in these patients.

All patients in our cohort with spinal-paraspinal

involve-ment by fast-flow lesions had clearly abnormal vascular

struc-tures on imaging; there were no examples of subtle lesions

with small arterial feeders. As such, we would expect that

cross-sectional imaging would be adequate as a screening tool

for patients with CLOVES and that in the absence of

intraspi-nal flow voids on MR imaging, spiintraspi-nal angiography for the sole

purpose of establishing the diagnosis appears to be

unnecessary.

Conclusions

Spinal-paraspinal fast-flow infiltrative lesions are a

rela-tively common cause of myelopathy in patients with CLOVES

syndrome. Heightened awareness of this association may

al-low earlier diagnosis.

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Figure

Fig 1.layer (bent arrowvia the C3, C4, and C5 segmental branches of the right vertebral artery
Fig 1 layer bent arrowvia the C3 C4 and C5 segmental branches of the right vertebral artery. View in document p.2
Fig 2. Airregular contour due to the intradural dilated vessels, with focal hyperintense changes

Fig 2.

Airregular contour due to the intradural dilated vessels with focal hyperintense changes. View in document p.3
Fig 3. A, Faint diffuse capillary stain covering asymmetrically thickened soft tissue of the back and scoliosis

Fig 3.

A Faint diffuse capillary stain covering asymmetrically thickened soft tissue of the back and scoliosis. View in document p.4

References

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